Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones

Definitions

• the invention encompasses solid composites of the calcium receptor-active compounds, processes for preparing the solid composites, immediate and controlled-release pharmaceutical formulations comprising the solid composites, and methods of treatment therewith.
• Cinacalcet hydrochloride has the chemical name (R)-N-[ 1 -(I -naphthyl)ethyl]-
• Cinacalcet hydrochloride is a calcium receptor-active compound that is currently marketed under the trade name SENSIP AR ® for the treatment of hyperparathyroidism in patients with chronic kidney disease on hemodialysis. Physicians ' Desk Reference, 60th ed. (2006), pp. 603-605.
• the dosing of SENSIP AR® is expressed in terms of amount of cinacalcet free base, (R)-N-[I -(I -naphthyl)ethyl]-3-[3-(trifluoromethyl) phenyl]propan-l -amine, present in the tablet, rather than in terms of the amount of the hydrochloride salt. See id.
• Cinacalcet is a solid that is understood to be slightly soluble in water and very soluble in some organic solvents, such as methanol and ethanol.
• U.S. Patent Application No. 10/937,870 published as U.S. Patent Application Publication No. 2005/0147669 (“the '669 publication”) reports that cinacalcet has a solubility in water of less than about 1 ⁇ g/ml at neutral pH.
• the '669 publication reports that the solubility of cinacalcet can reach about 1.6 mg/ml when the pH ranges from about 3 to about 5. However, when the pH is about 1, the solubility decreases to about 0.1 mg/ml. Id.
• the '669 publication addresses the poor water solubility of cinacalcet by providing pharmaceutical compositions comprising cinacalcet in the form of particles with a
• the present invention is directed to a composition, comprising a solid composite of cinacalcet in intimate association with at least one carrier.
• the composition is the solid composite.
• at least about 85 percent of the cinacalcet is in intimate association with the at least one carrier, at least about 85 percent of the cinacalcet is not in particulate form, at least about 85 percent of the cihacalcet is not in crystalline form, and/or the solid composite is a solid solution.
• substantially all of the cinacalcet is in solution in the solid solution.
• the carrier comprises a polymer, such as povidone, poloxamer, hydroxypropyl methylcellulose, polyethylene glycol, copovidone, copolymers of methacrylate, copolymers of methacrylic acid, and mixtures thereof.
• the polymer is povidone or a copolymer of methacrylic acid.
• the carrier comprises a sugar or sugar derivative, such as sucrose, mannitol, lactose, maltitol, sorbitol, xylitol, sucralose, and mixtures thereof.
• the solid composite is a particulate having an average particle size of more than about 100 ⁇ m, preferably, from about 100 to about 600 ⁇ m.
• the composite has a drug to carrier weight ratio of from about 1 :0.5 to about 1:10, preferably, from about 1:2 to about 1:6.
• the composition is a pharmaceutical formulation, comprising from about 10 percent to about 40 percent by weight of cinacalcet.
• the composition further comprises about 0.5 percent to about 5 percent by weight relative to the total weight of the formulation of at least one glidant or lubricant and/or about 1 percent to about 6 percent by weight of at least one coating material.
• the composition is an immediate release composition from which at least about 80 percent of the cinacalcet is released within about 30 minutes in 0.05 N HCl in a U.S.P. type 2 apparatus at a temperature of about 37°C and at a rotation speed of about 75 r.p.m.
• the composition is a controlled release pharmaceutical formulation, and wherein, when the formulation is exposed to a solution of 0.05 N HCl in a U.S.P. type 2 apparatus at a temperature of about 37°C and at a rotation speed of about 75 r.p.m. for about 30 minutes, followed by addition of a buffer in an amount sufficient to neutralize the solution and continued exposure to the neutralized solution, more than about 50 percent of the cinacalcet is released from the formulation within about the first 30 minutes of exposure, and not less than about 70 percent of the calcium receptor-active compound is released from the formulation within about the first 90 minutes of exposure.
• At least about 50 percent of the cinacalcet is released within about the first 60 minutes of exposure, more preferably, not less than about 80 percent of the cinacalcet is released from the formulation during about the first 90 minutes of exposure, and, most preferably, not less than about 90 percent of the cinacalcet is released from the formulation during about the first 90 minutes of exposure.
• the invention is directed to a method for preparing a solid composite, comprising combining cinacalcet, at least one carrier, and at least one liquid solvent to form a solution, and removing the solvent to obtain a solid composite of the cinacalcet and the at least one carrier.
• the solid composite is a solid solution.
• the carrier is selected from the group consisting of povidone, poloxamer, hydroxypropyl methylcellulose, polyethylene glycol, copovidone, copolymers of methacrylate, and copolymers of methacrylic acid, preferably at least one of lower aliphatic alcohols and C3-8 ketones.
• the solvent is removed by evaporation, preferably under vacuum, in a fluidized bed drier, or by spray drying.
• the composition is the cinacalcet and at least one carrier are dissolved in an organic or inorganic solvent to form the solution, a supercritical fluid is added to induce precipitation of a mixture of the cinacalcet and the carrier, and the solvent and the supercritical fluid are removed by evaporation.
• the solvent is a supercritical fluid, preferably, at least one of carbon dioxide, water, methane, ethane, propane, ethylene, propylene, methanol, ethanol, and acetone, and, more preferably, carbon dioxide.
• the supercritical fluid is removed by evaporation.
• the invention is directed to a method for preparing the solid composite, comprising combining cinacalcet and at least one carrier to form a mixture, heating the mixture to a temperature at which both the cinacalcet and the carrier melt to form a fusion product, and cooling the fusion product in a manner that does not allow crystallization of the cinacalcet out of the fusion product.
• the method further comprises combining the cinacalcet and at least one carrier to form a mixture, heating the mixture to control its viscosity, and feeding the heated mixture through a hot melt extrusion system.
• the invention is directed to a method of treatment, comprising administering an effective amount of a preferred composition of the invention to a mammal, such as a human.
• Figure 1 illustrates an XRD diffractogram of cinacalcet raw material.
• Figure 2 illustrates an XRD diffractogram of PVP K-30.
• Figure 3 illustrates an XRD diffractogram of a 1 :2 solid solution of cinacalcet with PVP K-30.
• Figure 4 illustrates an XRD diffractogram of EUDRAGIT ® L-100-55.
• Figure 5 illustrates an XRD diffractogram of a 1 :2 solid solution of cinacalcet with EUDRAGIT L-100-55.
• Figure 6 illustrates a DSC thermogram of cinacalcet raw material.
• Figure 7 illustrates a DSC thermogram of PVP K-30.
• Figure 8 illustrates a DSC thermogram of a 1:2 solid solution of cinacalcet with PVP K-30.
• Figure 9 illustrates a DSC thermogram of EUDRAGIT ® L-100-55.
• Figure 10 illustrates a DSC thermogram of a 1 :2 solid solution of cinacalcet with EUDRAGIT L-100-55.
• Figure 11 illustrates a dissolution profile of a solid solution of cinacalcet with
• PVP P-00709
• PVP P-00709
• PVP (1:3) PVP 1:3
• SENSIP AR ® SENSIP AR ®
• Figure 12 illustrates a dissolution profile of a solid solution of cinacalcet with
• PVP P-00709
• PVP aphysical mixture of cinacalcet with PVP (1 :3)
• SENSIP AR ® in 6 g/L NaH 2 PO 4 , pH 6, 0.15% SLS, USP apparatus 2, 37°C, 75 r.p.m.
• Figure 13 illustrates a dissolution profile of a 1 :2 solid solution of cinacalcet with EUDRAGIT ® and of SENSIPAR ® in 0.05 N HCl, U.S. P. type 2 apparatus, 37°C, 75 r.p.m.; and in 6 g/L NaH 2 PO 4 , pH 6, 0.15% SLS, USP apparatus 2, 37°C, 75 r.p.m.
• Figure 14 illustrates a dissolution profile of formulations of solid solutions of cinacalcet in a simulated gastrointestinal environment.
• cinacalcet means cinacalcet free base and pharmaceutically acceptable salts and solvates thereof.
• cinacalcet means cinacalcet hydrochloride.
• intimate association when used with respect to a mixture of cinacalcet and at least one carrier, means that the carrier(s) and the cinacalcet interact on the molecular level, there being no easily detectable separate cinacalcet phase.
• a non-intimate association is, for example, a powder blend, or a compressed powder blend, as it is possible to discern between different phases using, for example, electron microscopy.
• Another example of a non-intimate association is an emulsion, where separate phases co-exist in the solution, and may be visualized using, for example, a light microscope.
• An example for an intimate associations is a liquid solution, where there is no way to separate between the carrier and the solute by physical means, or to observe a phase of solute within the carrier.
• free drug means solid particles consisting essentially of cinacalcet that are not in intimate association with a carrier.
• non-crystalline and not in crystalline form means a material comprising cinacalcet that does not produce an X-ray powder diffraction pattern having peaks characteristic of crystalline cinacalcet, and that does not exhibit a discernable endotherm in differential scanning calorimetry using heating rates of 2 to 20 degrees per minute.
• a "solid solution” means a solid, homogenous mixture of at least two components (e.g. cinacalcet and a carrier) wherein the components are interspersed on a molecular level.
• the individual physical properties related to the crystalline structure of the components present in lesser amounts, commonly referred to as the solutes, are lost. Presence of the solutes can be detected spectroscopically or by measure of the colligative properties of the solid solution. Even in the solid solutions, some portion of the cinacalcet may come out of solution or remain undissolved in the carrier without departing from the scope of the invention. However, in the solid solutions, at least about 85 percent of the cinacalcet is in solution in the solid solution. Preferably, substantially all, and, most preferably, all, of the cinacalcet is in solution in the solid solution.
• the term "supercritical fluid” refers to substances at a temperature and pressure above their thermodynamic critical point.
• a supercritical fluid solution is a solution in which a supercritical fluid is the solvent.
• Such a substance has unique properties, such as the ability to diffuse through a solid like a gas, and dissolve solids like a liquid. Additionally, it is possible to change the density of such a substance by subtle changes in temperature and/or pressure.
• Useful supercritical fluids are, for example, carbon dioxide, water, methane, ethane, propane, ethylene, propylene, methanol, ethanol, and acetone.
• the supercritical fluid is selected from the group comprising carbon dioxide, water, and ethanol. More preferably, the supercritical fluid is carbon dioxide.
• treatment means at least one of the following: reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, or improvement or remediation of damage.
• the invention encompasses a solid composite comprising cinacalcet and at least one carrier, wherein at least about 85 percent of the cinacalcet is in intimate association with the carrier.
• the solid composite is a solid solution.
• substantially all of the cinacalcet is in solution in the solid solution. More preferably, all of the cinacalcet is in solution in the solid solution.
• the solid composite is particulate and has an average particle size larger than about 100 ⁇ m, more preferably between 100 and 600 ⁇ m.
• At least about 85 percent of the cinacalcet in the solid composite is not in crystalline form. More preferably, the cinacalcet in the solid composite has no detectable crystalline cinacalcet.
• the carrier may be any pharmaceutically acceptable inert solid carrier known to one of skill in the art, including, for example, sugars and polymers.
• the carrier is a hydrophilic polymer or a polymer presenting a pH dependent solubility profile in aqueous media.
• the hydrophilic polymer may be selected from the group consisting of povidone, poloxamer, hydroxypropyl methylcellulose, polyethylene glycol, copovidone, and amino alkyl methacrylate type A NF.
• the polymer presenting a pH dependent solubility profile in aqueous media may be selected from copolymers of methacrylic acid. More preferably, the carrier is povidone or a copolymer of methacrylic acid. Although hydroxypropyl methyl cellulose phthalate, polymethylacrylate, and hydroxypropyl cellulose may be used in the present invention as carriers, other carriers, particularly povidone and copolymers of methacrylic acid, are more preferred in the present invention.
• the carrier is present in an amount sufficient to maintain at least about 85 percent of the cinacalcet in intimate association with, and, more preferably, in solid solution in, the carrier.
• the drug-to-carrier weight ratio in the solid composites is within a range of about 1:0.5 to about 1:10, preferably about 1:2 to about
• the invention further encompasses a process for preparing the solid composite comprising: combining cinacalcet, at least one carrier, and at least one liquid solvent to form a solution; and removing the liquid solvent to obtain the solid composite.
• the cinacalcet may be prepared by any means known to one of skill in the art.
• Liquid solvents suitable for preparing the solid composite include organic solvents capable of dissolving at least about 85 percent of the cinacalcet and substantially all of the carrier.
• the liquid solvent is capable of dissolving at least about 85 percent of the cinacalcet and at least about 85 percent of the carrier. More preferably, the liquid solvent is capable of dissolving substantially all of the cinacalcet and carrier. Most preferably, the liquid solvent is capable of dissolving all of the cinacalcet and carrier.
• the liquid solvent is one in which cinacalcet has a solubility of at least about 5 mg of cinacalcet per 1 ml solvent at 25 0 C.
• liquid solvents include, but are not limited to, at least one of lower aliphatic alcohols and C 3 -8 ketones.
• Lower aliphatic alcohols as used herein means organic compounds having the general structure R-OH, wherein R is a linear or branched Cj -6 alkyl group.
• Preferred lower aliphatic alcohols include methanol, ethanol, isopropyl alcohol (“IPA”), and butanol.
• Preferred C 3-8 ketones include acetone, methylisobutyl ketone ("MIBK”) and methylethyl ketone (“MEK”).
• More preferred liquid solvents are " ethanol, acetone, isopropyl alcohol, and mixtures thereof.
• the liquid solvent is ethanol or mostly ethanol in combination with one or more of the above solvents.
• the combining step may include mixing the liquid solvent with cinacalcet and at least one carrier in any order.
• the cinacalcet, carrier, and liquid solvent may be mixed using any suitable mixing method known to one of skill in the art, such as by using magnetic stirrers, mixer stirrers, shakers, or sonif ⁇ cation.
• At least about 85 percent of the cinacalcet and a majority of the carrier are in solution in the at least one liquid solvent. More preferably, at least about 85 percent of the cinacalcet and about 85 percent of the carrier are in solution in the at least one liquid solvent. Even more preferably, substantially all of the cinacalcet and carrier are in solution in the at least one solvent. In particularly preferred embodiments, all of the cinacalcef and carrier are in solution in the at least one solvent.
• the step of removing the liquid solvent may be performed by any method known to one of skill in the art.
• the liquid solvent is removed by evaporation.
• the liquid solvent is removed by evaporation under vacuum, by fluidized bed drying, or by spray-drying.
• Spray-drying broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture.
• spray-drying apparatus there is a strong driving force for evaporation of solvent from the droplets, which may be provided by providing a heated drying gas.
• Spray-drying processes and equipment are described in Perry's Chemical
• the obtained solid composite may optionally be further dried.
• the obtained solid composite is in the form of a solid solution, wherein substantially all, most preferably all, of the cinacalcet is in solid solution in the carrier.
• the process further comprises the addition of at least one pharmaceutically acceptable excipient.
• suitable pharmaceutically acceptable excipients include, for example, surfactants such as sodium lauryl sulfate.
• the pharmaceutically acceptable excipient may be combined with the cinacalcet, carrier, and liquid solvent in step a), or may be added to the obtained solid composite of step b) after removal of the liquid solvent.
• the pharmaceutically acceptable excipient may be added during removal of the liquid solvent in step b), by, for example, spraying the solution containing the cinacaclet, carrier and solvent onto a fluidized bed of the excipient while drying.
• the solid composite will be formed on the excipient.
• this process will prove advantageous because it provides a solid composite with greater surface area, which can aid in dissolution in aqueous media upon administration to a patient.
• the invention further encompasses a process for preparing the solid composite using supercritical fluid technology.
• the process may comprise: dissolving cinacalcet and at least one carrier in a supercritical fluid; and removing the supercritical fluid by evaporation.
• the evaporation is accomplished under reduced pressure or by adjusting the temperature of the solution to a temperature at which the supercritical fluid becomes a gas.
• the process may comprise: dissolving cinacalcet and at least one carrier in an organic or inorganic solvent to form a liquid solution; adding a supercritical fluid (anti-solvent) to induce precipitation of a mixture of the cinacalcet and the carrier; and removing ' the solvent and the supercritical fluid by evaporation.
• the evaporation is accomplished under reduced pressure or by adjusting the temperature of the solution.
• the invention further encompasses a process for preparing the solid composite comprising: combining cinacalcet and at least one carrier to form a mixture; heating the mixture to a temperature at which both the cinacalcet and the carrier melt to form a fusion product; and cooling the fusion product in a manner that does not allow for re-crystallization of the cinacalcet out of the fusion product.
• the invention further encompasses a process for preparing the solid composite comprising: combining cinacalcet and at least one carrier to form a mixture, heating the mixture to control its viscosity; and feeding the heated mixture through a hot melt extrusion system.
• a larger particle size of the solid composite particles may be used in the formulation without • having an adverse effect on the dissolution profile of the cinacalcet.
• Another method to improve the safety of the products is by using a bi-modal distribution of particle sizes of the cinacalcet, wherein the population of large particle sizes, above 70 ⁇ m, avoids the need for micronization of the cinacalcet, and thus reduces production of hazardous dust.
• the population of small particle sizes smaller than about 5 ⁇ m, preferably less than 2 ⁇ m, and even more preferably smaller than l ⁇ m, is prepared using a high pressure homogenizer. This method involves micronizing the particles in a liquid medium, thus avoiding production and dispersion of dust particles of the active ingredient.
• the invention further encompasses pharmaceutical formulations comprising a solid composite comprising cinacalcet and at least one carrier, and at least one pharmaceutically acceptable excipient.
• the pharmaceutical formulation may contain additional cinacalcet, meaning free drug cinacalcet in addition to the cinacalcet in the solid composite, thus providing the ability to manipulate the dissolution characteristics of the formulation.
• the amount of the solid composite used in the pharmaceutical formulation is preferably an amount that provides a therapeutically effective amount of cinacalcet. It will be appreciated that the amount of solid composite used will differ according to the cinacalcet: carrier ratio in the particles.
• the pharmaceutical formulation comprises: (a) from about 10 percent to about 40 percent by weight of a calcium receptor-active compound, such as cinacalcet; (b) from about 10 percent to about 50 percent of at least one binder, which may serve as the carrier or "solid solvent" of the solid composite; (c) from about 15 percent to about 45 percent by weight of at least one diluent; and (e) from about 10 percent to about 40 percent of at least one disintegrant; wherein the percentage by weight is relative to the total weight of the formulation.
• a calcium receptor-active compound such as cinacalcet
• binder which may serve as the carrier or "solid solvent" of the solid composite
• diluent from about 15 percent to about 45 percent by weight of at least one diluent
• disintegrant from about 10 percent to about 40 percent of at least one disintegrant
• the formulation may further comprise about 0.5 percent to about 5 percent by weight relative to the total weight of the formulation of at least one glidant or lubricant and about 1 percent to 6 percent by weight of at least one coating material. It is understood by one of skill in the art that one or more inactive ingredients can act in more than one capacity for example; the same material may function as both a diluent and a disintegrant.
• the formulation may further comprise a surfactant.
• the pharmaceutical formulation can be processed into, for example, a unit dosage form.
• the pharmaceutical formulation can be formulated into oral solid dosage forms such as capsules, tablets, or gel-caps.
• the solid composites and pharmaceutical formulation including them preferably allow for the rapid absorption and onset of the calcium receptor-active compound cinacalcet in a mammal.
• the invention further encompasses an immediate release formulation of a calcium receptor-active compound, such as cinacalcet, wherein at least about 80 percent of the calcium receptor-active compound is released from the formulation within about 30 minutes in 0.05 N HCl in a U.S.P. type 2 apparatus at a temperature of about 37°C and at a rotation speed of about 75 r.p.m.
• a calcium receptor-active compound such as cinacalcet
• the invention further encompasses a controlled release formulation of a calcium receptor-active compound, such as cinacalcet, wherein the majority of the calcium receptor-active compound is released in the intestine, where the pH is slightly acidic to neutral, rather than in the stomach, where the pH is acidic.
• a calcium receptor-active compound such as cinacalcet
• the controlled release formulation When the controlled release formulation is exposed to a simulated gastric environment for a period of about 30 minutes, followed by exposure to a simulated intestinal environment, more than about 50 percent of the calcium receptor-active compound is released from the formulation during about the first 30 minutes of exposure and not less than about 70 percent of the calcium receptor-active compound is released from the formulation during about the first 90 minutes of exposure.
• At least about 50 percent of the calcium receptor-active compound is released within about the first 60 minutes of exposure, i.e., 30 minutes after the change in environment.
• not less than about 80 percent of the calcium receptor-active compound is released from the formulation during about the first 90 minutes of exposure.
• not less than about 90 percent of the calcium receptor-active compound is released from the formulation during about the first 90 minutes of exposure.
• the simulated gastric environment is 800 ml of 0.05 N HCl in a U.S.P. type 2 apparatus at a temperature of about 37°C and at a rotation speed of about 75 r.p.m.
• the simulated intestinal environment is 6 g/L NaH 2 PO- I , pH 6, 0.15% sodium lauryl sulfate in a
• the invention further encompasses a method of treatment comprising administering the pharmaceutical formulation to a mammal.
• the mammal is a human.
• the pharmaceutical formulation comprises cinacalcet and is administered to treat secondary hyperparathyroidism, which is the approved use for SENSIP AR ® .
• the method of "treating" secondary hyperparathyroidism described herein encompasses both prevention of the disorder in a predisposed individual and treatment of the disorder in a clinically symptomatic individual.
• the amount of calcium receptor-active compound administered and the dosing regimen used will depend on the particular drug selected, the age and general condition of the subject being treated, the severity of the subject's condition, and the judgment of the prescribing physician.
• dissolution profiles were determined in a dissolution vessel using a U.S.P. type 2 apparatus (paddles) in a simulated gastrointestinal environment under conditions described in Table 1. See U.S. Pharamcopeia, pp. 2155-2156 (26th ed. 2003). Samples were analyzed on-line by a UV detector.
• Example 1 Cinacalcet Solid Solutions with Povidone a " ) Cinacalcet HCl: povidone in 1:2 weight ratio
• X-ray diffraction (“XRD") and differential scanning calorimetry (“DSC”) were performed on the dry solid and compared to the XRD and DSC for the cinacalcet and povidone alone.
• the XRD and DSC for the dry solid are illustrated in Figures 3 and 8, respectively.
• the XRD and DSC for the cinacalcet are illustrated in Figures 1 and 6, respectively.
• the XRD and DSC for the povidone are illustrated in Figures 2 and 7, respectively.
• the amount of cinacalcet dissolved at the 30 minute time point demonstrates that cinacalcet in a solid solution form has a solubility greater than cinacalcet raw material in a physical mixture with lactose or starch.
• the percent of cinacalcet dissolved after 5 minutes demonstrates the greater dissolution rate of cinacalcet in a solid solution form, as compared with both SENSIP AR ® and a physical mixture of particles with an average length of 20 ⁇ m with starch.
• Ig of cinacalcet was dissolved in 10 ml of ethanol to form a first solution.
• 2 g of EUDRAGIT ® L- 100-55 was dissolved in about 15 ml of ethanol to form a second solution.
• DSC for the cinacalcet and EUDRAGIT ® L-100-55 alone The XRD and DSC for the dry solid are illustrated in Figures 5 and 10, respectively.
• the XRD and DSC for the cinacalcet are illustrated in Figures 1 and 6, respectively.
• L-100-55 are illustrated in Figures 4 and 9, respectively.
• cinacalcet was released more quickly from the SENSIP AR® tablets than from the solid solution of cinacalcet and EUDRAGIT ® L-100-55. For example, about 95 percent of the cinacalcet was released from the SENSIP AR ® tablets during about the first 30 minutes of exposure ' to the 0.05N HCl, while only about 15 percent of the cinacalcet was released from the solid solution of cinacalcet and EUDRAGIT ® L-100-55 the under the same conditions.
• Example 3 Formulation including cinacalcet solid solution with povidone
• Example 4 Formulation including cinacalcet solid solution with povidone
• a solid solution of cinacalcet with povidone (1 :2 weight ratio) prepared according to Example Ia was passed through a sieve equipped with a 30 mesh ( ⁇ 600 micron aperture) screen on top of a 50 mesh screen (300 micron aperture).
• the sample which passed the 50 mesh screen, is estimated to have a particle size distribution wherein approximately 100 percent of the particles are less than 300 microns in size and an average particle size around 100 ⁇ m.
• This sample was used to prepare a pharmaceutical formulation of cinacalcet, with a target amount of 90 mg of cinacalcet per tablet, having the following composition:
• Example 5 Formulation including cinacalcet solid solution with EUDRAGIT L-100-55
• a solid solution of cinacalcet in EUDRAGIT ® L- 100-55 (1 :2 weight ratio) prepared according to Example 2 was passed through a sieve equipped with a 30 mesh screen on top of a 50 mesh screen.
• Cinacalcet HC1:EUDRAGIT ® L-100-55 with Average Particle Size of -400 urn [0099] The solid composite collected on top of the 50 mesh screen (having a particle size between 300 ⁇ m and 600 ⁇ m) was used in a pharmaceutical formulation (average particle size estimated to be ⁇ 400 ⁇ m).
• the solid composite which passed through the 50 mesh screen (having a particle size distribution wherein 100 percent of the particles are less than 300 ⁇ m in size) was used in another pharmaceutical formulation (average particle size estimated to be -lOO ⁇ m).
• Each solid composite (5a and 5b) was used to prepare a pharmaceutical formulation of cinacalcet, with a target amount of 90 mg of cinacalcet per tablet, having the following composition:
• Example 6 Dissolution profile of tablet formulations of cinacalcet
• the dissolution profiles of the formulations prepared in Examples 4 and 5 were measured with a U.S.P. type 2 apparatus at a temperature of about 37 0 C 3 and at a rotation speed of about 75 r.p.m.
• the dissolution profiles are described in Table 5 and illustrated in Figure 14. Percentage of dissolution was adjusted to change in medium volume.
• the dissolution profile was measured in a complex medium designed to imitate physiological conditions in the gastrointestinal tract.
• the medium was 800 ml 0.05N HCl, which was then neutralized with 120 ml of a neutralizing buffer (50 g/1 NaH 2 PO 4 adjusted to pH 6, to which were added 35 ml/1 IO N NaQH, and 11.25 g/1 SLS) for a final volume of 920 ml.
• a neutralizing buffer 50 g/1 NaH 2 PO 4 adjusted to pH 6, to which were added 35 ml/1 IO N NaQH, and 11.25 g/1 SLS
• Example 7 Method for improving the safety of cinacalcet production - Preparation of sub-micron scale population of particles
• a suspension of cinacalcet hydrochloride in water is placed in a Micro fluidics
• D 50 particle size is less than about I ⁇ m.
• This population is mixed with a population of particles having a D 50 of more than about 100 ⁇ m, so that the overall particle size D 50 is larger than about 70 ⁇ m.
• This mixture is then used in a formulation, and the dissolution profile is examined.
• Example 8 Preparation of cinacalcet solid solutions using supercritical fluid technology
• a solution of cinacalcet in absolute ethanol, also containing PVP K-30, is introduced in the particle formation vessel of a supercritical apparatus containing supercritical carbon dioxide at an appropriate flow through the inner nozzle passage.
• Supercritical carbon dioxide is introduced at an appropriate flow through the outer nozzle passage.
• a solid fluffy substance is formed, and the pressure lowered to remove the carbon dioxide and ethanol.

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• 2007
  • 2007-08-30 CA CA002662315A patent/CA2662315A1/en not_active Abandoned
  • 2007-08-30 BR BRPI0715635-9A patent/BRPI0715635A2/pt not_active Application Discontinuation
  • 2007-08-30 EP EP07837587A patent/EP1945184A2/de not_active Withdrawn
  • 2007-08-30 JP JP2009526733A patent/JP2010501642A/ja active Pending
  • 2007-08-30 WO PCT/US2007/019151 patent/WO2008027522A2/en active Application Filing
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  • 2007-08-30 CN CNA200780037397XA patent/CN101522173A/zh active Pending
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• 2009
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